Platelet function and bleeding in chronic lymphocytic leukemia and mantle cell lymphoma patients on ibrutinib

Abstract

Background: Therapy with irreversible Bruton's tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is associated with bleeding. Objectives: To propose the predictive markers of such bleeding, as well as mechanisms responsible for decreased bleeding at later therapy stages. Patients/Methods: We investigate platelet functional activity in 50 CLL and 16 MCL patients on ibrutinib using flow cytometry and light transmission aggregometry. Results: Prior to treatment, both patient groups had decreased platelet counts; impaired aggregation with adenosine diphosphate (ADP); and decreased binding of CD62P, PAC1, and annexin V upon stimulation. Bleeding in patients treated with ibrutinib was observed in 28 (56%) CLL patients, who had decreased aggregation with ADP and platelet count before therapy. Their platelet count on therapy did not change, platelet aggregation with ADP steadily improved, and aggregation with collagen first decreased and then increased in anticorrellation with bleeding. Bleeding in MCL was observed in 10 (62%) patients, who had decreased dense granule release before therapy. ADP and ristocetin induced platelet aggregation in ibrutinib-treated MCL patients increased on therapy, while collagen-induced aggregation evolved similarly to CLL patients. Conclusions: Our results suggest that ibrutinib-dependent bleeding in CLL patients involves three mechanisms: decreased platelet count (the most important discriminator between bleeding and non-bleeding patients), impaired platelet response to ADP caused by CLL, and inhibition by ibrutinib. Initially, ibrutinib shifts the balance to bleeding, but then it is restored because of the improved response to ADP. | 2673 DMITRIEVA ET Al.

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

“…The highest risk of haemorrhage occurs in the first months of treatment, suggesting that both disease and treatment-related factors influence the severity of this AE (Ysebaert et al, 2014;Lipsky et al, 2015;Brown et al, 2019;Dmitrieva et al, 2020). Furthermore, patients with B-cell malignancies have an intrinsic risk of bleeding (Gifkins et al, 2015).…”

“…Low-grade bleeding events are usually not associated with thrombocytopenia, suggesting an impaired platelet function as the cause of the AE as reviewed (Berglöf et al, 2015). However, Dmitrieva et al (2020) investigated the platelet function in 50 CLL and 16 MCL patients and their results suggest that ibrutinibdependent bleeding in CLL patients requires a setting of three mechanisms. Most important was a decreased platelet count prior ibrutinib treatment.…”

Procoagulant Platelets: Mechanisms of Generation and Action

“…83,84 Ibrutinib treatment further reduced procoagulant platelet formation upon strong stimulation, which was already reduced in patients with chronic lymphocytic leukemia which could also contribute to the development of bleeding. 85 On the other hand, recent study suggests that procoagulant platelets are upregulated by desmopressin and may play a role in its mechanism of action of desmopressin. 86 Another study 87 showed the ability of procoagulant platelets to bind factor VIIa and promote factor X activation by it, which may be a mechanism of action of recombinant-activated factor VII.…”

Platelets and cancer… the plot doesn’t always thicken

“…Consideration of bleeding risk is therefore increasingly needed in oncological practice. In this edition of the journal, Dmitrieva and colleagues explore the timing of bleeding risk and platelet dysfunction in lymphoproliferative disorders treated with the first‐in‐class Bruton's tyrosine kinase (BTK) inhibitor ibrutinib 3 …”

“…Dmitrieva and colleagues examined platelet dysfunction over time during ibrutinib treatment 3 . They found that platelet function decreased following initiation of ibrutinib, but then improved in concert with disease response.…”